Our major goals for this project are to determine the relationship between two categories of genetic factors, HLA class II alleles and T cell receptor (TCR) genomic polymorphisms, and both the development and expression of rheumatoid arthritis (RA). In order to accomplish these goals, we will determine the frequencies of specific HLA class II alleles and TCR genomic polymorphisms among a group of Caucasian females with RA who have been followed for up to ten years, and a group of age and sex matched controls without RA. The expression of RA will be defined in terms of several categories of RA manifestations including serologic and laboratory measures, radiographic outcomes, extraarticular manifestations, functional status, and medication responses and toxicities. We will compare the frequencies of specific HLA alleles, TCR genomic polymorphisms, and combinations of these genetic factors between different RA subgroups to determine whether these genetic factors are associated with the expression of RA. Similarly, we will compare the frequencies of these same genetic factors between RA cases and controls to determine whether these genetic factors are associated with susceptibility to RA. Two aspects of this project will project will provide us with a unique opportunity to address questions which have not previously been fully examined. The fact that we will study a group of RA patients whose disease has been characterized over many years of illness will allow us to examine the relationship of genetic factors to a broad range of long- term outcomes. Further, by characterizing study participants in terms of two genetic factors which are both believed to play an important role in RA, we can determine the relative and combined importance of these factors in determining the development and expression of RA. The results of this study may lead to important advances in our understanding of the immunologic mechanisms underlying the pathogenesis of RA. Such knowledge may eventually form the basis of more specific immunotherapy for RA. Further, by increasing our understanding of the relationship of these genetic factors to RA expression, the results of this study may lead to improvements in our ability to predict the prognosis and likely course of illness, and hence our ability to individualize the management of RA.